Project Summary: Alzheimer's disease (AD) is the most common type of dementia currently affecting more than 4 million people in the United States alone. It has been estimated that delaying the onset of the disease by only 5 years could result in a 50% decrease in disease prevalence. Therefore, identification of people at risk prior to the clinical appearance of dementia has become a priority due to the potential benefit from therapeutic or preventative intervention. Recently, our lab and others have demonstrated regional increased rates of cerebral atrophy several years before elderly people reach the stage known as mild cognitive impairment. Although these observations are consistent with the presence of a preclinical stage of AD, the mechanism(s) responsible for this observation are unknown. In this proposal we will investigate the relationship between cerebral atrophy rates, iron homeostasis and tissue micro structural complexity. Specifically, we are interested in whether disruption of brain iron homeostasis and reduction in tissue micro structural complexity are evident prior to the onset of clinically relevant cerebral atrophy. To test these hypotheses, we will conduct longitudinal and cross-sectional studies in cognitively intact individuals, subjects with mild cognitive impairment (MCI), and patients with mild AD. We will use well established MRI techniques (T2, T2* and DTI) along with two novel quantitative MRI techniques;Magnetic Field Correlation (MFC) imaging and Diffusional Kurtosis Imaging (OKI). Relevance: The questions to be addressed in this proposal are whether complex aspects of AD pathology can be given a precise definition suitable for quantitative evaluation, and what such an evaluation can contribute to our understanding of the disease. The ability to quantitatively assess regional brain iron homeostasis and tissue micro structural complexity in AD patients noninvasively and longitudinally has potential use in (a) studying the pathogenesis of AD, (b) monitoring disease progression, and (c) aiding in the differential diagnosis of AD. Moreover, this work will allow us to identify presymptomatic persons who are most likely to benefit from early intervention, help develop surrogate markers, accelerate drug discovery, and provide an objective, noninvasive means to monitor therapeutic trials. Given the incidence of neurodegenerative disease, the potential impact of this study is considerable.